PROJECT SUMMARY ? PROJECT 3 New therapies are desperately needed for esophageal cancer, which is responsible for >400,000 deaths annually. Herein we propose to build on momentum from our prior studies, founded on our observation that the most prominent genomic targets in esophageal cancer, both squamous cell carcinoma (ESSC) and adenocarcinoma (EAC), are amplifications of genes encoding mediators of the cell cycle such as CCND1=Cyclin D1 (collaboration with Project 3) and CCNE1=Cyclin E1 and genes encoding receptor tyrosine kinases such as EGFR (collaboration with Project 1) and ERBB2. Given this genomic landscape, a key premise of our work has been that developing therapeutic approaches that integrate targeting of both active kinases and cell cycle dysregulation will be remarkably beneficial. While these data, hypotheses and premises all continue to hold true, we now propose a more nuanced assessment of how cell cycle dysregulation may impact tumorigenesis and optimal cancer therapy. Specifically, we hypothesize that amplification and overexpression of Cyclin D1 and Cyclin E1 can have effects upon the tumor microenvironment and upon genomic stability, both of which have clear implications for optimal therapy. This hypothesis will be pursued through the following interrelated Specific Aims: (1) To determine how CDK4/6 inhibitors impact the tumor microenvironment in CCND1-amplified esophageal squamous cell carcinoma and to define enhanced immune therapy strategies; and (2) To elucidate how CCNE1 amplification promotes chromosomal instability, kinase amplification and immune evasion in esophageal adenocarcinoma. Together, these studies will help us develop rationale, biomarker-guided therapies for these deadly cancers. This work will be done in close collaboration with Projects 1 and 2 to drive presentations, publications and transform the clinical landscape of esophageal cancer, and to utilize the core facilities in an integrated fashion with the other Projects.